TAK-063, a phosphodiesterase 10A inhibitor, modulates neuronal activity in various brain regions in phMRI and EEG studies with and without ketamine challenge

Abstract

TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3mg/kg (26% PDE10A occupancy in rats) or higher in rodents through the balanced activation of the direct and indirect pathways of striatal medium spiny neurons (MSNs). In this study, we evaluated the specific binding of TAK-063 using in vitro autoradiography (ARG) and the modulation of brain activity using pharmacological magnetic resonance imaging (phMRI) and electroencephalography (EEG). [H]TAK-063 significantly accumulated in the caudate-putamen (CPu), ventral pallidum (VP), substantia nigra (SN), hippocampus (Hipp), and amygdala (Amy), but not in the frontal cortex (Fcx), brainstem (Bs), or cerebellum (Cb) in an ARG study using rat brain sections. [H]TAK-063 accumulation in the CPu was more than eighteen-fold higher than that in the Hipp and Amy. TAK-063 at 0.3mg/kg increased the blood oxygenation level-dependent (BOLD) signal in the striatum and Amy, and decreased it in the Fcx in a phMRI study with anesthetized rats. TAK-063 at 0.3mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2mg/kg (35% PDE10A occupancy in monkeys) also reduced the ketamine-induced increase in EEG gamma power in awake monkeys. In line with the EEG data, TAK-063 at 0.3mg/kg reversed the ketamine-induced BOLD signal changes in the cortex, Bs, and Cb in a phMRI study with anesthetized rats. These data suggest that TAK-063 at about 30% PDE10A occupancy modulates activities of multiple brain regions through activation of neuronal circuits in rats and monkeys.

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

“…Immunohistochemical study also supports this idea: TAK‐063 at 0.3 and 3 mg/kg p.o. increased c‐Fos expression in subregions of the medial prefrontal cortex, anterior cingulate cortex, and prelimbic cortex in rats where the specific binding of [ 3 H]TAK‐063 was not observed in the ARG study . These data suggest that TAK‐063 modulates activities of cortical regions through activation of neuronal circuits in rats and monkeys.…”

“…Besides antipsychotic‐like effects, differential activation pattern of MSNs may also affect other pharmacological properties of PDE10A inhibitors. Interestingly, different from TAK‐063, MP‐10 did not significantly inhibit ketamine‐induced increase in EEG gamma power and did not produced cognitive improvement in novel object recognition task in rats . Differential activation pattern of MSNs may affect the modulation of cortical activity by PDE10A through the striato‐thalamo‐cortical circuit.…”

“…To evaluate the effects of TAK‐063 on cortical activity, electroencephalography (EEG) and pharmacological magnetic resonance imaging (phMRI) studies were conducted. NMDAR antagonist ketamine‐induced increase in gamma power was dose dependently and significantly suppressed by TAK‐063 in rats and monkeys . In phMRI study, TAK‐063 (0.3 and 3 mg/kg i.p.)…”

“…NMDAR antagonist ketamine-induced increase in gamma power was dose dependently and significantly suppressed by TAK-063 in rats and monkeys. 53 In phMRI study, TAK-063 (0.…”

TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington’s Disease

“…associated with the output functions such as motor and cognitive responses, including procedural learning and cognitive flexibility (Tanimura et al, 2008). Pharmacological magnetic resonance imaging and electroencephalography studies suggest that TAK-063 most likely modulates cortical activity through corticalstriatal-thalamic circuits (Tomimatsu et al, 2016). Therefore, in addition to neuroprotective effects of TAK-063, modulation of cortical functions through the corticostriatal circuit may also contribute to the improvement of cognitive function of R6/2 mice in the procedural water T-maze test.…”